Association of FMRP with Ribosomal Precursor Particles in the Nucleolus

Willemsen, Rob; Bontekoe, Carola; Tamanini, Filippo; Galjaard, H.; Hoogeveen, André T.; Oostra, Ben A.

doi:10.1006/bbrc.1996.1126

Cited by 69 publications

(53 citation statements)

References 22 publications

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“…Ribosomal association with FMRP is mRNA-dependent and requires several other proteins to be present, forming a large ribonucleoprotein particle. FMRP has also been localized in the nucleus of neurons as well (15,(17)(18)(19)(20). As a whole, these data suggest that FMRP is related to mRNA transport from the nucleus to the dendrites and may play a role in protein synthesis in dendrites and synapses.…”

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confidence: 65%

Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice

Wilson

Cox

2007

Proc. Natl. Acad. Sci. U.S.A.

106

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Fragile X syndrome is a common heritable form of mental retardation in humans. Recent neuroanatomical studies indicate an apparent immature appearance of neurons in fragile X syndrome patients and fragile X mental retardation protein (FMRP)-knockout mice, an animal model of this condition. In this work, we investigated possible alterations in synaptic plasticity in the neocortex of FMRP-knockout mice. Extracellular field potentials were recorded from the deep-layer visual neocortex. Long-term potentiation (LTP) was severely attenuated in brain slices from knockout mice relative to that observed in slices from wild-type mice. Considering that neocortical LTP can involve both NMDA receptor-dependent and -independent mechanisms, we attempted to distinguish the nature of LTP attenuated in the knockout condition. In slices from wildtype mice, LTP was partially attenuated by the NMDA receptor antagonist 3-[(؎)-2-carboxypiperazin-4-yl]-propyl-1-phosphate (CPP); however, the general metabotropic glutamate receptor (mGluR) antagonist ␣-methyl-4-carboxyphenylglycine (MCPG) strongly attenuated LTP, resulting in a response indistinguishable from that observed in slices from knockout mice. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) attenuated LTP to a similar degree as did MCPG in wild-type slices, but MPEP did not alter the reduced potentiation in knockout slices. Our results suggest that LTP in layer V visual neocortex depends primarily on mGluR5 activation. Our data also indicate that mGluR5-mediated synaptic plasticity is absent in the neocortex of FMRPknockout mice. Such an alteration may contribute to the cognitive and learning deficits exhibited in these mice as well as in fragile X syndrome.fragile X mental retardation protein ͉ long-term potentiation ͉ synaptic plasticity ͉ visual cortex F ragile X syndrome is the most frequent cause of familial mental retardation and is a prevalent cause of mental disability second only to Down's syndrome, affecting Ϸ1 in 4,000 males and 1 in 8,000 females (1-3). Fragile X syndrome is linked to a large variety of phenotypic characteristics, including increased incidence of autistic behavior, attention-deficit disorder, anxiety disorder, sensory-processing problems, epilepsy, delays in speech and language development, and macroorchidism (4, 5). This syndrome results from the lack of fragile X mental retardation (FMR1) gene expression and the corresponding absence of its protein product, fragile X mental retardation protein (FMRP). The lack of FMRP has been correlated with mental impairment ranging from mild learning disabilities to profound mental retardation (6-8). At present, there is no cure for this syndrome, but it is extremely important to understand the consequences of the absence of FMRP to the nervous system as well as other body systems.FMRP is expressed most abundantly in neurons and is concentrated within dendritic spines, and at the subcellular level the protein is primarily found associated with both cytoplasmic and endoplasmic reticulum...

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confidence: 65%

Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice

Wilson

Cox

2007

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Although nucleolin is normally localized to the nucleolus, a significant pool of it is cytoplasmic (5,8,45). Conversely, FMRP, while largely cytoplasmic, has been found in the nucleolus (42). Thus, only a fraction of the cellular nucleolin may be associated with FMRP.…”

Section: Discussionmentioning

confidence: 99%

Isolation of an FMRP-Associated Messenger Ribonucleoprotein Particle and Identification of Nucleolin and the Fragile X-Related Proteins as Components of the Complex

Ceman

Brown

Warren

1999

Molecular and Cellular Biology

160

144

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The loss of FMR1 expression due to trinucleotide repeat expansion leads to fragile X syndrome, a cause of mental retardation. The encoded protein, FMRP, is a member of a gene family that also contains the fragile X-related proteins, FXR1P and FXR2P. FMRP has been shown to be a nucleocytoplasmic shuttling protein that selectively binds a subset of mRNAs, forms messenger ribonucleoprotein (mRNP) complexes, and associates with translating ribosomes. Here we describe a cell culture system from which we can isolate epitopetagged FMRP along with mRNA, including its own message, and at least six other proteins. We identify two of these proteins as FXR1P and FXR2P by using specific antisera and identify a third protein as nucleolin by using mass spectrometry. The presence of nucleolin is confirmed by both reactivity with a specific antiserum as well as reverse coimmunoprecipitation where antinucleolin antiserum immunoprecipitates endogenous FMRP from both cultured cells and mouse brain. The identification of nucleolin, a known component of other mRNPs, adds a new dimension to the analysis of FMRP function, and the approach described should also allow the identification of the remaining unknown proteins of this FMRP-associated mRNP as well as the other bound mRNAs.Fragile X syndrome is a common form of inherited mental retardation. It is caused by a loss of expression of the FMR1 gene, most often due to an expansion of a CGG repeat in the first exon (reviewed in references 2 and 41). Although this region is untranslated, repeat expansion leads to abnormal methylation and chromatin deacetylation, which results in transcriptional silencing of FMR1 (9,18,28,30,39). The FMR1 gene encodes an approximately 78-kDa protein, FMRP, although multiple isoforms exist due to alternate splicing (1). FMRP contains two hnRNP K-homologous (KH) domains and an RGG box, motifs thought to mediate interactions with mRNA (13). Indeed, FMRP has been shown to bind its own mRNA, homopolymer RNA in vitro, and a subset of brain mRNAs (3,7,35). In addition, FMRP is associated with ribosomes in an RNA-dependent manner (12,40). When lysates were treated with EDTA to dissociate the ribosomal subunits, FMRP was released as a large (greater than 669-kDa) messenger ribonucleoprotein (mRNP) particle containing both poly(A) ϩ mRNA and protein (12,14). Such mRNP complexes are thought to be formed in the cytoplasm after the hnRNP proteins, which associate with the mRNA in transit from the nucleus to the cytoplasm, are released and exchanged for cytoplasmic proteins (11). Some cytoplasmic RNA binding proteins, however, are identical to those found in the nucleus (17). Thus, some proteins seem to remain associated with mRNAs regardless of where the complex is located in the cell. FMRP contains both a functional nuclear localization signal (NLS) and a nuclear export signal (12, 38), and although it is primarily cytoplasmic at steady state, about 5% of the cellular FMRP is nuclear (15). FMRP is therefore believed to shuttle between the nucleus and cytoplasm, compa...

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“…This X-linked disorder is caused by the absence of the fragile X mental retardation protein (FMRP). FMRP expression is widespread with abundant expression in neurons and trafficking to dendrites in particular and with testicular expression in spermatogonia (3,14,15,38,43). The association of FMRP with ribosomes is mRNA dependent via ribonucleoprotein (RNP) particles, which contain several other proteins including the fragile X (structurally)-related proteins FXR1P and FXR2P (10).…”

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confidence: 99%

Transport of Fragile X Mental Retardation Protein via Granules in Neurites of PC12 Cells

Otero

Severijnen

Cappellen

et al. 2002

Molecular and Cellular Biology

Self Cite

134

109

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Lack of fragile X mental retardation protein (FMRP) causes fragile X syndrome, a common form of inherited mental retardation. FMRP is an RNA binding protein thought to be involved in translation efficiency and/or trafficking of certain mRNAs. Recently, a subset of mRNAs to which FMRP binds with high affinity has been identified. These FMRP-associated mRNAs contain an intramolecular G-quartet structure. In neurons, dendritic mRNAs are involved in local synthesis of proteins in response to synaptic activity, and this represents a mechanism for synaptic plasticity. To determine the role of FMRP in dendritic mRNA transport, we have generated a stably FMR1-enhanced green fluorescent protein (

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Association of FMRP with Ribosomal Precursor Particles in the Nucleolus

Cited by 69 publications

References 22 publications

Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice

Absence of metabotropic glutamate receptor-mediated plasticity in the neocortex of fragile X mice

Isolation of an FMRP-Associated Messenger Ribonucleoprotein Particle and Identification of Nucleolin and the Fragile X-Related Proteins as Components of the Complex

Transport of Fragile X Mental Retardation Protein via Granules in Neurites of PC12 Cells

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